Research concerning the mode of action of antidepressant compounds has indicated that prolonged drug treatment leads to desensitization (i.e. decreased responsiveness) of brain alpha2 adrenoceptors. Based partly on this finding, a "dysregulation" theory for the etiology of depressive illness was recently put forward (1). That theory suggests, in part, that a trait vulnerability for depressive illness could be due to a faulty regulation of feedback-inhibitory alpha2 adrenoceptors in the brain. An assessment of alpha2 adrenoceptors from depressed patients may therefore provide a genetic marker for depressive illness. My proposal will assess whether alpha2 adrenoceptors as readily characterized on platelets, might offer the substrate for developing such a marker. In a study with 20 depressed patients and 20 controls, I hop to provide preliminary evidence for measurement of platelet alpha2 adrenoceptors as a useful marker for either the diagnosis, treatment and/or prevention of relapse for depressed patients. My approach will be unique from earlier studies which have reported equivocal findings on a link between platelet adrenoceptors and clinical indices of depression (18). Earlier studies reported only single time "static" measurements of adrenoceptor status. Instead, I propose to study the dynamic process of agonist-induced adrenoceptor desensitization. My studies will use 3H-para-aminoclonidine to compare the rate and maximal degree of adrenoceptor desensitization in platelet suspensions between patients and controls. It will be attempted to ascertain (A) whether desensitization is altered in platelets from untreated patients compared to untreated controls, (B) whether desensitization changes following treatment with desipramine, and (C) whether there are differences in alpha2 adrenoceptor desensitization between responders and non- responders to treatment with DMI.